The ultimate goal of this application is to determine the cause(s) of type 2 diabetes and other states of abnormal glucose metabolism. We wish to do so in order to develop rational approaches for the prevention and treatment of these disorders. The role of the liver in the evolution of type 2 diabetes has not been as extensively studied as that of muscle. The present application will focus on gaining a greater understanding of the regulation of hepatic glucose metabolism in non-diabetic humans and the contribution of alterations in hepatic insulin action (in conjunction with alterations in extra-hepatic insulin action and insulin secretion) to the pathogenesis of type 2 diabetes. Specific aim I will seek to validate a potentially simpler and more physiologic method of assessing insulin action by determining whether hepatic and extrahepatic insulin action measured with a newly developed labeled "meal" minimal model is equivalent to that measured in the same individuals with a traditional hyperinsulinemic euglycemic clamp. Individuals with either isolated fasting or combined fasting and post-prandial hyperglycemia are at high risk of developing overt diabetes. Specific aim II will use the data derived from Specific aim I to determine whether the site (hepatic vs. extrahepatic), severity, and cause (glycogenolysis vs. gluconeogenesis) of insulin resistance differs in people with isolated fasting or combined fasting and postprandial hyperglycemia. We also will use sophisticated models of insulin secretion to determine whether defects in the kinetic response to glucose and/or changes in incretin secretion contribute to hyperglycemia in these individuals. Local cortisol production in fat and/or the liver by 11 beta-hydroxysteroid dehydrogenase type 1 has recently emerged as a potentially important regulator of hepatic insulin action. Specific aim III will use a novel cortisol tracer method combined with splanchnic catheterization to determine whether splanchnic conversion of cortisone to cortisol occurs in humans, whether the rate of conversion is increased by obesity or diabetes, and whether this conversion contributes to the hepatic insulin resistance of obesity and type 2 diabetes. Excess free fatty acids (FFA) can cause insulin resistance in non-diabetic humans and are commonly elevated in type 2 diabetes. Specific aim IV will re-examine the mechanism(s) by which elevated FFA cause hepatic insulin resistance in non-diabetic humans, will determine whether elevated FFA alter insulin induced suppression of glucose production in diabetic humans, and if so, whether this is due to changes in glycogenolysis, gluconeogenesis and/or hepatic glycogen synthesis. This specific aim also will seek to determine whether treatment with a thiazolidinedione blunts or prevents FFA induced hepatic (and extrahepatic) insulin resistance, and whether the effects of FFA on insulin action are influenced by gender.